The mesolimbic pathway through the release of dopamine from neurons in the ventral tegmental area (VTA), which project to the nucleus accumbens (NAc), is thought to have a role in motivation and reward processes. Some addictive drugs produce their potent effects on behavior by enhancing mesolimbic dopamine activity. Release of dopamine from VTA neurons is controlled by various factors and neuronal structures. One pathway providing regulatory input to the VTA originates in the mesopontine nuclei of the brainstem. We have previously shown that the mesopontine-VTA-NAc pathway is modulated by the novel neuropeptide urotensin II (Uil). To facilitate our studies we have developed and validated a fusion of diphtheria toxin with UN (Dtx-Uli). This toxin is able to selectively ablate Ull-R expressing neurons of the mesopontine without damage to surrounding tissue. Through the combination ofthis toxin with microdialysis and behavioral paradigms (self-administration and conditioned place preference), we will establish whether Uil can modulate reinforced behaviors. In addition, to better understand the function ofthe mesopontine nuclei, the Dtx-Uli will be used to ablate neurons of this region. Subsequently, different aspects of proposed mesopontine function will be tested ( ex. prepulse inhibition, conditioned place preference). Drug addiction is a multifactorial condition. This heterogeneity is partly due to genetic predisposition. Any gene that is expressed in the neuronal circuitry known to modulate the acquisition and maintenance of addiction could impact the development of an addiction, although that gene may not be the direct target of the drug. Uil is an emerging neuromodulator which may have implications in addiction and the development of addiction. Furthermore, in other work UN has been shown to produce cellular remolding, which may point to a role in neuroplasticity. Therefore, future studies will include the investigation ofthe role of Ull-R in molecular neurobiological changes and the development of addiction.